In 1998 we proposed an alternative to the broadly accepted Two Stage pathophysiologic hypothesis associated with preeclampsia. In contrast to the view that abnormal placentation results in the release of one or more placental toxins leading to maternal endothelial injury and systemic disease, we proposed that an identifiable prepregnancy physiologic phenotype predisposes to preeclampsia when pregnancy specific physiologic adaptations are superimposed. We suggested that low prepregnancy plasma volume was an important marker for those at risk and that volume expansion was the critical pregnancy specific physiologic stressor. Since that time significant evidence, from multiple lines of investigation, has supported the hypothesis that prepregnancy phenotype contributes importantly to the risk for preeclampsia and that reduced plasma volume is predictive of those at risk. In our recently completed studies we have demonstrated the significant association of prepregnancy physiology with many of the presumed pathophysiologic consequences of pregnancy complicated by preeclampsia; including reduced uterine blood flow in early pregnancy, increased pulse pressure, and reduced third trimester plasma volume. That research effort, summarized in our progress report, was aimed at demonstrating that prepregnancy physiology contributes importantly to maternal physiology observed during pregnancy. Based on preliminary data acquired in those studies we now propose that a combination of prepregnancy physiology and the unique physiologic adaptations of pregnancy contribute to the development of preeclampsia and its associated pathologic findings. Examining women at risk for the development of preeclampsia and initiating studies prior to pregnancy we will demonstrate, in three specific aims; 1. That low plasma volume, low uterine blood flow and increased arterial pulse pressure, prior to pregnancy, are associated with an increased risk of developing preeclampsia and its pathphysiologic associations. 2. a) That the renal response to pregnancy, reflected by changes in renal blood flow and the renin angiotensin system will be a function of plasma volume prior to pregnancy. b) That changes in markers of vascular endothelial injury, from prior to pregnancy through the third trimester, are strongly associated with volumetric renal blood flow changes and renal artery shear stress during the course of pregnancy; and these responses will be predicted by prepregnancy renal vasodilatory capacity. 3. That normal pregnancy predisposes women to increases in posterior cerebral edema in the third trimester and that this edema is exacerbated in association with elevated systemic blood pressure in late pregnancy. PUBLIC HEALTH RELEVANCE: The goal of this grant is to examine the contribution of prepregnancy physiologic phenotype to the development of preeclampsia. In addition, we are looking to understand the influence of pregnancy- specific, physiologic adaptations to the pathophysiologic associations of preeclampsia in a group of women at risk for developing preeclampsia.